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Local delivery of CAR T cells targeting fibroblast activation protein is safe in patients with pleural mesothelioma: first report of FAPME, a phase I clinical trial

Open ArchivePublished:October 21, 2020DOI:https://doi.org/10.1016/j.annonc.2020.10.474
      Malignant pleural mesothelioma (MPM) is a cancer derived from mesothelial cells growing in the thoracic cavity with few treatment options. Despite the use of multi-modality approaches, the median survival after diagnosis does not exceed two years.
      • Stahel R.A.
      • Riesterer O.
      • Xyrafas A.
      • et al.
      Neoadjuvant chemotherapy and extrapleural pneumonectomy of malignant pleural mesothelioma with or without hemithoracic radiotherapy (SAKK 17/04): a randomised, international, multicentre phase 2 trial.
      Adoptive cell transfer of genetically engineered chimeric antigen receptor (CAR) T cells has shown great success in hematological malignancies,
      • Schuster S.J.
      • Bishop M.R.
      • Tam C.S.
      • et al.
      Tisagenlecleucel in adult relapsed or refractory diffuse large B-cell lymphoma.
      but are still under investigation in solid tumors. Due to the confined spread of MPM, local delivery of CAR T cells might overcome a major challenge in CAR T cell treatment, namely successful homing to the tumor tissue.
      Here, we report the data of the first phase I clinical trial (NCT01722149) using fibroblast activation protein (FAP) targeting CAR T cells (CART-FAP)
      • Gulati P.
      • Ruhl J.
      • Kannan A.
      • et al.
      Aberrant Lck signal via CD28 costimulation augments antigen-specific functionality and tumor control by redirected T cells with PD-1 blockade in humanized mice.
      injected into the pleural cavity of MPM patients. FAP is highly expressed on all MPM subtypes
      • Petrausch U.
      • Schuberth P.C.
      • Hagedorn C.
      • et al.
      Re-directed T cells for the treatment of fibroblast activation protein (FAP)-positive malignant pleural mesothelioma (FAPME-1).
      including the patients reported in this trial, but not on healthy adult tissues. The aim of the study was to determine the toxicity and feasibility of this treatment. All patients included had histologically or cytologically confirmed metastatic MPM and were medically and/or functionally not inaccessible for surgical treatment, with all patients receiving three cycles of chemotherapy before CART-FAP administration. All patients had adequate bone marrow, hepatic and renal function, without corticosteroids treatment. Four patients were included in this trial; one patient did not receive CAR T cells due to low expansion rate after retroviral transduction. Patients were continuously monitored for the first 48 h after CART-FAP transfer. Safety assessments included incidence of treatment-related adverse events, according to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) 4.0. In two patients, a thromboembolic event occurred and resolved; these events were considered unrelated to study treatment but possibly to active cancer, chemotherapy or the presence of an indwelling catheter. Safety board evaluation felt the study could continue after review (Table 1). We injected one million CART-FAP cells; this is the lowest recommended dose for second generation CAR T cells (CD28 signaling domain)
      • Ertl H.C.
      • Zaia J.
      • Rosenberg S.A.
      • et al.
      Considerations for the clinical application of chimeric antigen receptor T cells: observations from a recombinant DNA Advisory Committee Symposium held June 15, 2010.
      and it has been selected as FAP has not been previously investigated as a target. Although this subtherapeutic dose, we detected systemic expansion of CART-FAP cells in the blood peaking in one out of three patients at 21 days after intrapleural infusion. This finding indicates that a local administration of CART-FAP can lead to systemic distribution. Furthermore, all CAR T cell products were proven to be highly specific in vitro and this translated to elevated concentrations of proinflammatory cytokines in patients' sera, indicating an ongoing immune response.
      Table 1Feasibility of FAP CAR T cells production and toxicity after administration
      FeasibilityPatient 1Patient 2Patient 3
      CAR T cell generation
       Day 2 PBMC CD3+ (%)50.4562.1038.60
       Day 9 CD8+ fraction in the positive fraction (%)23.3087.0081.80
       Day 9 FAP recognizing in the positive fraction (%)51.7553.0358.60
       Day 9 CD8+ after expansion (%)4.8036.2037.11
      Clinical course
       Time to progression after CAR T cell infusion12 Months9 MonthsResponding after 18 months
       CAR T cells responding to FAP by IFNγ releaseYesYesYes
       CAR T cells detected in the bloodYesNoNo
      ToxicityGrade 1Grade 2Grade 3Grade 4Total
      AE
       Hematologic events
      CD4 lymphocytes reduced01102
      Lymphopenia21104
       Non-hematologic events
      Respiratory, thoracic and mediastinal disorders, other leak thorax drain01001
      Thromboembolic event00101
      Upper respiratory infection01001
      Total24309
      SAE
       Non-hematologic events
      Upper respiratory infection01001
      Thromboembolic event00202
      Total01203
      AE, adverse event; CAR, chimeric antigen receptor; FAP, fibroblast activation protein; IFN, interferon; PBMC, peripheral blood mononuclear cell; SAE, serious adverse event.
      A single infusion of CART-FAP cells was safe. Due to the trial design and small number of patients we could not evaluate the impact of this treatment on patient outcome (supplementary File available at https://doi.org/10.1016/j.annonc.2020.10.474); however, we could confirm the in vitro activity and functionality of CART-FAP cells. Future clinical trials will allow better understanding of existing barriers and improve the efficacy of cellular therapies in solid tumors. To the best of our knowledge, this is the first completed clinical trial reporting the use of this approach in patients with MPM.

      Acknowledgements

      The authors thank all the patients and their families, the nurses and technicians involved in this clinical trial at the University Hospital Zurich for their great collaboration and care. We thank the Wyss Center Zurich for the GMP accordant transport, the Clinical Trial Center (CTC) at the University Hospital Zurich for the monitoring of the study.

      Funding

      This work was supported by the Forschungskredit University of Zurich [grant number 54171101 ]; Swiss Cancer League [grant number KFS-3115-02-2013 ]; Cancer Research Institute ; Ludwig Institute for Cancer Research ; and the funding initiative ‘Hoch-spezialisierte Medizin Schwerpunkt Onkologie und Schwerpunkt Immunologie (HSM-2-Immunologie)’ of the Canton Zurich , Switzerland.

      Disclosure

      The authors have declared no conflicts of interest.

      Supplementary data

      Figure thumbnail figs1
      Supplementary figure 1_resubmission

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